MICROALBUMINURIA COME MARCATORE DI RISCHIO CARDIOVASCOLARE. Michele Meschi

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1 MICROALBUMINURIA COME MARCATORE DI RISCHIO CARDIOVASCOLARE Michele Medicina Interna a Indirizzo Nefro-Cardiovascolare Ospedale «Santa Maria» di Borgo Val di Taro Azienda USL Parma

2 Evidence points to a major role for the RAAS in pathophysiologicalchanges that lead to progressive renal and cardiovascular disease Renin inhibitor Angiotensinogen Renin AngI ACEIs ACE Compensatory feedback ARBs AngII AT 1 receptor Reactive oxygen species Inflammatory mediators (e.g. IL-6) Adhesion molecules (e.g. IL-6) Cellular growth and apoptosis Aldosterone Aldosterone inhibitor Endothelial dysfunction ALBUMINURIA Basi S, Am J Kidney Dis Nefro 2013

3 Albuminuria De Jong PE, Curhan GC. J Am Soc Nephrol 17: , 2006 Nefro 2013

4 Urinary PROTEIN excretion < 150 mg/die 300 mg/die physiological microproteinuria (urinary dipstick non detectable) overt proteinuria PCR > 200 mg/g De Jong PE, Curhan GC. J Am Soc Nephrol 17: , 2006 Nefro 2013

5 Quando ricercare albuminuria e proteinuria? L escrezione urinaria di albumina e di proteine deve essere quantificata, sia nei diabetici che nei non diabetici, quando egfr < 60 ml/min/1.73 m 2 ; il primo risultato anomalo dev essere confermato con un campione mattutino Stesso atteggiamento nei confronti dei soggetti con egfr > 60 ml/min/1.73 m 2 ma per i quali si ha sospetto di nefropatia cronica Linee Guida ISS Min Sal SIN 2012 Nefro 2013

6 Mortalità per tutte le cause e per malattie cardiovascolari Fragilità e cognitive impairment ACR 265 mg/g oppure PCR 442 mg/g p 3a: ml/min/1.73 mq 3b: ml/min/1.73 mq Linee Guida ISS Min Sal SIN 2012 Nefro 2012

7 Mortalità per tutte le cause e per malattie cardiovascolari Fragilità e cognitive impairment STADIO 3 STADIO 3b Incremento di rischio per eventi cardiovascolari Incremento di mortalità generale e di mortalità per malattie cardiovascolari (eccesso di rischio) Incremento di rischio per fragilità e declino cognitivo p Fattore di rischio indipendente per mortalità generale Fattore di rischio indipendente per stroke Linee Guida ISS Min Sal SIN 2012 Nefro 2013

8 Association with all-cause mortality of GFR and UAE Cirillo M et al, J Nephrol 2012 Nefro 2013

9 MAU is an early, sub-clinical sign of target-organ damage and is correlated with specific cardio-renal outcomes Clinical disease Subclinical organ damage CV event Risk factors CV = cardiovascular. Microalbuminuria (MAU) End organ failure Dzau VJ, Circulation Nefro 2012

10 Key clinical studies evaluating the predictive value of MAU on CV risk MAU as a predictor Year Study name Author/s Title Patient # 2000 WESDM 2001 HOPE 2002 PREVEND 2003 UKPDS Valmadrid CT, Gerstein HC, Hillege HL, Adler Al, The risk of CV disease mortality associated with microalbuminuria and gross proteinuria in persons with older-onset diabetes mellitus. Albuminuria and risk of CV events, death, and heart failure in diabetic and non-diabetic individuals. Prevention of Renal and Vascular End Stage Disease (PREVEND) Study Group. Urinary albumin excretion predicts CV and non CV mortality in the general population. Development and progression of nephropathy in type 2 diabetes: The UK Prospective Diabetes Study (UKPDS 64). N=840 N=3498 N=85,421 N=5, LIFE Ibsen H, Reduction in albuminuria translates to reduction in CV events in hypertensive patients: losartan intervention for endpoint reduction in hypertension study. N=8, Framingham Heart Study Arnlöv J, Low-grade albuminuria and incidence of CV disease events in non-hypertensive and non-diabetic individuals. N=1, CHARM Jackson CE, Albuminuria in chronic heart failure: prevalence and prognostic importance. N=2, MAGIC Viazzi F, Microalbuminuria is a predictor of chronic renal insufficiency in patients without diabetes and with hypertension: the MAGIC study. N= ONTARGET Schmieder R, Changes in albuminuria predict mortality and morbidity in patients with vascular disease. N=23,480

11 Composite CV endpoint rates stratified baseline albuminuria measurement(uacr) The LIFE study Endpoint rate (%) <3 mg/mmol (n=2435, 1708, 1760) mg/mmol (n=1591, 1587, 1814) 1-3 mg/mmol (n=2219, 1827, 1946) 0.5 mg/mmol (n=1961, 3385, 2458) Month Reducing UACR is associated with a reduction in CV events in patients with hypertension Ibsen H, Hypertension. 2005;45: Nefro 2012

12 The ONTARGET/TRANSCEND study programme A) CV death decrease >50% vs minor change minor change increase >100% vs minor change < B) Composite CV endpoint decrease >50% vs minor change minor change increase >100% vs minor change < C) Combined renal endpoint decrease >50% vs minor change minor change increase >100% vs minor change Adjusted HR* (95 CI%) of changes in UACR from baseline to 2 year visit The risk of CV and renal outcomes is increased significantly if MAU is increased and is decreased if MAU is reduced Schmieder RE, JASN 2011 Nefro 2012

13 Increase in risk according to renal variables in ADVANCE Impact of renal variables on risk of CV and renal events OR* UACR (10-fold), CV 2.48 ( ) egfr (50%), CV 2.20 ( ) UACR >300 mg/g + egfr <60 ml/min, CV 3.20 ( ) UACR >300 mg/g + egfr <60 ml/min, renal 22.2 ( ) Risk reduction Risk increase * Multivariate adjusted (also for regression dilution). CV = cardiovascular; UACR = urinary albumin:creatinine ratio; egfr = estimated glomerular filtration rate. Ninomiya T, ADVANCE Collaborative Group. J Am Soc Nephrol. 2009;20: Nefro 2012

14 Understanding the clinical and epidemiological implications of MAU The RAAS plays a major role in development of albuminuria MAU is a strong and independent risk factor for cardio-renal disease UACR and egfr are multiplicatively and independently associated with mortality risk without evidence of interaction Albumin is a continuous predictor of mortality starting at low levels, whereas egfr is predictive only above a certain threshold Reducing proteinuria/mau leads to a decreased risk in CV and renal outcomes and all-cause mortality Nefro 2012

15 When to screen? Guideline recommendations for MAU testing Organisation Patient Group Frequency ESH-ESC Guidelines 2009 Reappraisal All people with: Hypertension (SBP 140 mmhg or DBP 90 mmhg) Metabolic syndrome & high-normal BP (SBP mmhg or DBP mmhg) Routine assessment at screening for CV risk and during treatment Patient should be assessed routinely using: Serum creatinine Estimated creatinine clearance Urinalysis (complemented by MAU via dipstick test and microscopic examination) Electrocardiogram MAU should be examined during treatment as well as during screening Current ESH-ESC guidelines recommend routine testing for MAU in patients with hypertension and in metabolic syndrome with high-normal BP 1. Mancia G, J Hypertens. 2007;25: Mancia G, J Hypertens. 2009;27:

16 Availability, prognostic value and cost of some markers of organ damage (scored from 0 to 4 pluses) Markers CV predictive val Availability Cost Electrocardiography Echocardiography Carotid Intima-Media Thickness Arterial stiffness (Pulse wave velocity) Ankle-Brachial index Coronary calcium content Cardiac/Vascular tissue composition? + ++ Circulatory collagen markers? + ++ Endothelial dysfunction Cerebral lacunae/white matter lesions? Est. GFR or ClCr Microalbuminuria Nefro 2012

17 Il 21% della popolazione generale dispone di un GFR calcolato L 11% dei pazienti diabetici e ipertesi dispone di un rapporto Alb/Creat Nefro 2012